Abstract Current state-of-the-art treatment of rheumatoid arthritis (RA) is not curative and is associated with considerable toxicity. Bone erosion and cartilage damage are the most severe complications of RA and the major reasons for pain and disability in this disease. They are also key targets that are resistant to current therapies. Substantial evidence now exists that mesenchymal stem cells (MSC) have regeneration ability and immunomodulatory functions that could contribute to treatment of autoimmune diseases. Nonetheless, it is unknown whether MSC, particularly those derived from gingival tissues (GMSC) can directly affect bone and cartilage protection. Based on our preliminary observations, we make a bold hypothesis that GMSC can directly inhibit the formation of osteoclasts and activities of inflamed synovial tissues and through these mechanisms can prevent bone erosion and cartilage damage in rheumatoid arthritis. The study will include two phases (R61 and R33) with three specific aims. For the R61 phase, specific aim 1 and 2 will test the hypothesis that GMSC suppress osteoclast differentiation and activities, as well as activation and function of inflamed synovial tissues in the in vitro and in vivo with collagen-induced arthritis (CIA) model and in the R33 phase (Specific aim 3) a further validation will be conducted using a humanized model. When successfully completed, this project will help us understand the characteristics of GMSC in protecting bone erosion and cartilage damage in autoimmune arthritis and may lead to a potential therapeutic strategy for RA and other human autoimmune diseases.